The prevalence of both juvenile (type 1) and adult onset (type 2) diabetes mellitus and its accompanying morbidity, complications, and costs for health care are increasing worldwide. The metabolic hallmarks of diabetes are hyperglycemia, elevated blood glucagon levels, impaired insulin secretion, and a loss of insulin sensitivity (insulin resistance). In type 1 diabetes the beta-cells that make insulin are markedly reduced by immune destruction. In type 2 diabetes the beta- cell mass is typically reduced by 50 percent or more and the remaining beta-cells fail to over-produce insulin to maintain euglycemia in the presence of insulin resistance. The goal of our studies is to understand how beta-cells develop from progenitor cells and to explore means to stimulate their differentiation and proliferation so as to restore the reduced beta-cell mass in diabetic individuals. The exocrine and endocrine pancreas (islets of Langerhans) are derived from a common progenitor cell during embryonic development. The endocrine cells undergo a progressive differentiation into distinct cell lineages that become the alpha, beta, and delta-cells that produce glucagon, insulin, and somatostatin, respectively. It is believed that the embryogenesis and the neogenesis of islet cells is programmed by the temporal and spatial expression of transcription factors, predominantly homeodomain and "helix-loop-helix" proteins. The expression of these key transcription factors is controlled by growth factors, i.e. morphogens or hormones. We hypothesize that the progenitor cells destined to become mature hormone-producing cells of the islets, such as the beta-cells that produce insulin, remain intact in diabetes. We seek an understanding of the factors involved in the commitment of progenitor cells to differentiate into mature hormone-producing endocrine cells. Here we propose studies directed to fulfill three aims: examination of the Pouhomeodomain protein Brain-4 as a potential key regulator of alpha-cell development and the expression of the glucagon gene; (2) investigations of glucagon-like peptide hormones as potential beta-cell morphogens; and (3) the isolation of novel GLP-1 receptors that may counteract the insulin resistance of diabetes. We propose that the results forthcoming from the experimental plan presented may provide insights into the design of rational, novel therapeutic approaches for the treatment and possibly an eventual cure for diabetes mellitus.